CD8 positive cytotoxic T lymphocytes (CTLs) have been shown to recognize epitope peptides derived from the tumor-associated antigens (TAAs) found on the major histocompatibility complex (MHC) class I molecule, and then kill the tumor cells. Since the discovery of the melanoma antigen (MAGE) family as the first example of TAAs, many other TAAs have been discovered, primarily through immunological approaches (NPL 1, 2). Some of these TAAs are currently undergoing clinical development as immunotherapeutic targets.
TAAs which are indispensable for proliferation and survival of cancer cells are valiant as targets for immunotherapy, because the use of such TAAs may minimize the well-described risk of immune escape of cancer cells attributable to deletion, mutation, or down-regulation of TAAs as a consequence of therapeutically driven immune selection. Accordingly, the identification of new TAAs capable of inducing potent and specific anti-tumor immune responses, warrants further development. Thus, the clinical application of peptide vaccination strategies for various types of cancer is ongoing (NPL 3-10). To date, there have been several reports of clinical trials using these tumor-associated antigen derived peptides. Unfortunately, so far, these cancer vaccine trials have yielded only a low objective response rate has been observed in these cancer vaccine trials so far (NPL 11-13). Accordingly, there remains a need in the art for new TAAs suitable for use as immunotherapeutic targets.
The KIF20A gene (RAB6KIFL) has been first identified to play a role in the dynamics of the Golgi apparatus through direct interaction with Rab6 small GTPase (NPL 14). KIF20A belongs to the kinesin superfamily of motor proteins, which have critical functions in trafficking of molecules and organelles (NPL 15, NPL 16, NPL 17). Recently, Taniuchi K et al. reported that KIF20A was overexpressed in pancreatic cancer tissues (NPL 18). They found evidence for a critical role of KIF20A in pancreatic carcinogenesis.
Through gene expression profile analysis using a genome-wide cDNA microarray containing 23,040 genes, KIF20A was recently shown to be up-regulated in several cancers such as bladder cancer (PTL 1), small cell lung cancer (SCLC) (PTL 2) and hormone-refractory prostate cancer (HRPC) (PTL 3), the disclosures of which are incorporated by reference herein. Further, some epitope peptides of KIF20A gene products were also identified (PTL 4).
Taken together, this data suggests that KIF20A is a novel, potentially universal oncoantigen. Accordingly, epitope peptides derived from KIF20A may be applicable as cancer immunotherapeutics for the treatment of a wide array of cancers.
Recently, highly immunogenic KIF20A-derived cytotoxic T lymphocytes (CTL)-epitopes that can induce tumor-reactive and HLA-A2 (A*02:01)-restricted CTL from PBMCs of healthy volunteers (NPL 19, PTL 5) have been identified. Furthermore, KIF20A-derived HLA-A24-restricted CTL-epitopes have been also identified (PTL 6). Therefore, KIF20A remains an attractive target molecule applicable to cancer immunotherapy.
Tumor-specific CD4+ helper T (Th) cells, especially T-helper type 1 (Th1) cells play a critical role in efficient induction of CTL-mediated antitumor immunity (NPL 20). The IFN-gamma primarily produced by Th1 cells is critical for induction and maintenance of long lived CTL responses, providing help through multiple interactions which are critical in the preservation of immunological memory (NPL 21, 22). The IFN-gamma secreted by Th1 cells also mediates direct antitumor or anti-angiogenic effect (NPL 23). Furthermore, it has been shown that Th cells must pave the way for entry of CTLs at tumor site (NPL 24). Therefore, identification of tumor-associated antigen (TAA)-derived Th cell epitopes that can activate specific Th1 cell is important for induction of an effective tumor immunity in tumor-bearing hosts; ideally, the design of effective vaccines should include multiple epitopes to stimulate both CTL and Th1 cells (NPL 25). However, no such epitope derived from KIF20A has yet been identified.